Systems and methods for driving nebulizers

ABSTRACT

In various arrangements, a nebulizer element of a nebulizer may be energized with a drive signal. A phase offset of the drive signal may be measured. A phase delta may be determined. The phase delta may indicate a difference between a target phase offset and the measured phase offset. The target phase offset may indicate a non-zero target phase difference between the voltage of the drive signal and the current of the drive signal. A frequency of the drive signal may be changed to decrease the phase delta.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/017,531, filed Sep. 4, 2013, entitled “Systems and Methods ForDriving Nebulizers,” attorney docket no. 78816-876735 (012620US) whichis a continuation-in-part of U.S. application Ser. No. 13/384,579, filedJan. 17, 2012, entitled “Systems and Methods for Driving SealedNebulizers,” attorney docket no. 015225-012610US, which is herebyincorporated by reference for all purposes.

U.S. application Ser. No. 13/384,579 claims the benefit of U.S.Provisional Patent Application No. 61/226,591, filed Jul. 17, 2009,entitled “Systems and Methods for Driving Sealed Nebulizers,” attorneydocket number 015225-012600US, and of International ApplicationUS/2010/042473, filed Jul. 19, 2010, entitled “Systems and Methods forDriving Sealed Nebulizers,” attorney docket number 015225-012600PC, theentire disclosures of both applications are hereby incorporated byreference for all purposes.

BACKGROUND

Embodiments of the present invention relate to nebulizers. Inparticular, the present invention relates to use of a variable frequencydriver for a nebulizer.

A wide variety of procedures have been proposed to deliver a drug to apatient. In some drug delivery procedures the drug is a liquid and isdispensed in the form of fine liquid droplets for inhalation by apatient. A patient may inhale the drug for absorption through lungtissue. Further, the droplets forming the atomized mist may need to bevery small to travel through small airways of the lungs. Such a mist maybe formed by a nebulizer.

SUMMARY

In some embodiments, a method for driving a nebulizer element of anebulizer is presented. The method may include energizing the nebulizerelement of the nebulizer with a drive signal. The method may includemeasuring a phase offset of the drive signal. The phase offset mayindicate a phase difference between a voltage of the drive signal and acurrent of the drive signal. The method may include, based on themeasured phase offset of the drive signal, adjusting a frequency of thedrive signal that energizes the nebulizer element such that the phaseoffset of the drive signal is maintained within a threshold range of apredefined phase offset.

Embodiments of such a method may involve one or more of the following:The method may include adjusting a voltage magnitude of the drive signalbased on a change in frequency of the drive signal over time. Thevoltage magnitude may be adjusted based on a table of predeterminedvoltage magnitudes. The table may be selected based on a type of liquidstored in a reservoir of the nebulizer. Energizing the nebulizer elementof the nebulizer with the drive signal may cause a liquid to beatomized. The liquid may be a medicine.

In some embodiments, the method for driving a nebulizer element of anebulizer is presented. The method may include energizing the nebulizerelement of the nebulizer with a drive signal. The method may includemeasuring a phase offset of the drive signal. The phase offset mayindicate a phase difference between a voltage of the drive signal and acurrent of the drive signal. The method may include determining a phasedelta. The phase delta may indicate a difference between a target phaseoffset and the measured phase offset. The target phase offset mayindicate a non-zero target phase difference between the voltage of thedrive signal and the current of the drive signal. The method may includechanging a frequency of the drive signal to decrease the phase delta.

Embodiments of such a method may involve one or more of the following:Changing the frequency of the drive signal to decrease the phase deltavalue may include one or more of the following: changing the frequencyof the drive signal to decrease the phase delta to less than a thresholdphase delta in a high gain mode; determining the phase delta is lessthan the threshold phase delta; and at least partially in response todetermining the phase delta is less than the first threshold phasedelta, changing the frequency of the drive signal to decrease the phasedelta in a low gain mode. The low gain mode may result in a smallerfrequency change than the high gain mode.

Additionally or alternatively, embodiments of such a method may involveone or more of the following: The method may include measuring animpedance of the nebulizer element. Changing the frequency of the drivesignal in the low gain mode is conditioned on the impedance of thenebulizer element not exceeding an impedance threshold. The method mayinclude determining a slope of the phase offset. Changing the frequencyof the drive signal in the low gain mode may be conditioned on the slopeof the phase offset being negative. The phase delta threshold may befive degree or less. The method may include adjusting the voltagemagnitude of the drive signal based on a change in frequency of thedrive signal over time. The target phase offset between the voltage ofthe drive signal and the current of the drive signal may be between 25degrees and 35 degrees. The target phase difference between the voltageof the drive signal and the current of the drive signal may be 30degrees. Energizing the nebulizer element of the nebulizer with thedrive signal may cause a liquid to be atomized. The liquid may be amedicine.

In some embodiments, a nebulizer system is presented. The nebulizersystem may include a liquid reservoir that is adapted to hold a liquidthat is to be atomized. The nebulizer system may include a nebulizer,comprising an element having a plurality of apertures. The element maybe configured to vibrate to atomize liquid drained from the liquidreservoir. The element may be driven by a drive signal. The nebulizersystem may include a driver. The driver may include a frequencygenerator. The driver may include a phase shift detector configured tomeasure a phase offset of the drive signal. The phase offset mayindicate a phase difference between a voltage of the drive signal and acurrent of the drive signal. The driver may include a processor. Theprocessor may be configured to determine a phase delta. The phase deltamay indicate a difference between a target phase offset and the measuredphase offset. The target phase offset may indicate a non-zero targetphase difference between the voltage of the drive signal and the currentof the drive signal. The processor may be configured to change afrequency of the drive signal output by the frequency generator todecrease the phase delta.

Embodiments of such a nebulizer system may include one or more of thefollowing: The processor being configured to change the frequency of thedrive signal output by the frequency generator to decrease the phasedelta may include the processor being configured to: change thefrequency of the drive signal output by the frequency generator todecrease the phase delta to less than a threshold phase delta in a highgain mode; determine the phase delta is less than the threshold phasedelta; and at least partially in response to determining the phase deltais less than the first threshold phase delta, change the frequency ofthe drive signal output by the frequency generator to decrease the phasedelta in a low gain mode. The low gain mode may result in a smallerfrequency change than the high gain mode. The processor may be furtherconfigured to calculate an impedance of the nebulizer element. Theprocessor changing the frequency of the drive signal output by thefrequency generator in the low gain mode may be conditioned on theimpedance of the nebulizer element being below an impedance threshold.

Additionally or Alternatively, embodiments of such a nebulizer systemmay include one or more of the following: The processor may be furtherconfigured to determine a slope of the phase offset. The processorchanging the frequency of the drive signal output by the frequencygenerator in the low gain mode may be conditioned on the slope of thephase offset being negative. The phase delta threshold may be fivedegree or less. The processor may be further configured to adjust thevoltage magnitude of the drive signal output by the driver based on achange in frequency of the drive signal over time. The target phaseoffset between the voltage of the drive signal and the current of thedrive signal may be between 25 degrees and 35 degrees. The target phasedifference between the voltage of the drive signal and the current ofthe drive signal may be 30 degrees. Energizing the nebulizer element ofthe nebulizer with the drive signal may cause a liquid to be atomized.The liquid may be a medicine.

BRIEF DESCRIPTION OF THE DRAWINGS

A further understanding of the nature and advantages of the presentinvention may be realized by reference to the following drawings. In theappended figures, similar components or features may have the samereference label. Further, various components of the same type may bedistinguished by following the reference label by a second label thatdistinguishes among the similar components. If only the first referencelabel is used in the specification, the description is applicable to anyone of the similar components having the same first reference labelirrespective of the second reference label.

FIG. 1A illustrates a simplified embodiment of a nebulizer.

FIG. 1B illustrates a simplified embodiment of a nebulizer with a driverunit.

FIG. 1C illustrates a simplified embodiment of a handheld nebulizer withan integrated driver unit.

FIG. 1D illustrates a nebulizer integrated with a ventilator.

FIG. 2 illustrates a simplified embodiment of a driver coupled with anebulizer.

FIG. 3 illustrates a method of driving a nebulizer with a driver.

FIG. 4 illustrates a method of initially determining a resonantfrequency of a nebulizer element.

FIG. 5 illustrates a simplified method of adjusting the frequency outputby a driver using a resonant frequency tracker to maintain the nebulizerelement vibrating at its current resonant frequency.

FIG. 6 illustrates another embodiment of a driver coupled with anebulizer.

FIG. 7 illustrates an embodiment of a graph illustrating phase offsetand impedance of a nebulizer element when excited by a drive signal atdifferent voltage frequencies.

FIG. 8 illustrates an embodiment of a method for maintaining a phaseoffset of a nebulizer drive signal.

FIG. 9 illustrates an embodiment of a method for setting and maintaininga phase offset of a nebulizer drive signal.

DETAILED DESCRIPTION

Devices, systems, and methods are described for the implementation of anovel architecture for driving a nebulizer. Various embodiments fordriving nebulizers at the nebulizers' resonance frequencies or otheroff-resonance frequencies (possibly based on phase) are presented. Insome embodiments, nebulizers with sealed drug reservoirs capable ofdeveloping a negative bias pressure (meaning the pressure within thereservoir is less than the pressure outside of the reservoir) as liquidis evacuated from the drug reservoir are presented. Embodiments detailedherein are also directed to driving a nebulizer element off-resonancesuch that a phase offset between the current and voltage of the signalused to drive the nebulizer element is maintained. For example, anon-zero phase offset between the current and voltage of the drivesignal may be maintained such that a nebulizer element is driven at anoff-resonance operating frequency. Various conditions involving theslope of the phase and/or the slope of the impedance (as the frequencyof the drive signal is varied) may be required to be satisfied such thatan operating frequency associated with a predefined phase offset is usedto drive the nebulizer element. Additional conditions may additionallyor alternatively need to be satisfied, such as maximum and/or minimumimpedance thresholds.

By creating a negative bias pressure within the drug reservoir of anebulizer, the efficiency of a nebulizer may be increased, thus allowingfor higher liquid flow rates of liquid atomized, possibly with smallerand more consistent droplet sizes than in comparable conditions withouta negative bias pressure. Such a negative bias pressure may be createdby sealing the drug reservoir. As the liquid drug is drained from thedrug reservoir (with little to no air entering to replace the drug'svolume), a negative bias pressure, compared with the outside atmosphericpressure, may be created within the reservoir. While the negative biaspressure may assist in maintaining consistently sized droplets of mist,as the negative bias pressure decreases in pressure, the flow rate ofliquid from the nebulizer may increase and/or a resonance frequency ofthe nebulizer element may shift.

An increased flow rate caused by a negative bias pressure may lead tothe wrong dose of a medicine being delivered to a patient and/or thegeneration of improper droplet sizes. Such improper droplet sizes mayalter how the droplets are absorbed into the human body. For example, ifa patient inhales droplets that are too large, the droplets may notpropagate into the deep lung tissue of the patient, but rather, thedroplets may gather in the patient's larger airways. This may preventproper absorption of the medicine's droplets by the patient.

Variances in flow rate may be additionally or alternatively caused byattempting to operate at or near a resonant frequency. While a firstflow rate may be realized while the nebulizer element is being vibratedat a resonant frequency, if the resonant frequency of the nebulizerelement changes, a second flow rate, which may be less than the firstflow rate, may result when the nebulizer element is vibratedoff-resonance. Therefore, if the nebulizer element vibrates at aresonant frequency, but the resonant frequency changes, the flow ratefrom the nebulizer element may be difficult to monitor, maintain, and/orpredict.

Droplets may be created from a stored amount of liquid in the drugreservoir by a nebulizer element. The nebulizer element may have anumber of small holes. When an electrical signal (referred to as thedrive signal), such as a waveform, is applied to the nebulizer element,the nebulizer element may vibrate at or near the frequency of thewaveform received. While vibrating, the nebulizer element may allow anamount of the liquid to pass through the holes on the element and formairborne droplets. The nebulizer element may function more efficientlyand produce consistent droplet sizes when the nebulizer element isvibrating at or near a resonant frequency of the nebulizer element.

The nebulizer element may be driven near a resonant frequency or at someother off-resonance frequency. Driving near a resonant frequency or atsome other frequency off-resonance, rather than at the resonantfrequency, may result in desirable operating characteristics. Driving anebulizer element off-resonance may provide a more consistent flow rateof atomized liquid than attempting to drive the nebulizer element on aresonant frequency. While driving directly on a resonant frequency ofthe nebulizer element may result in a higher flow rate of atomizedliquid, it may be difficult to maintain vibration of the nebulizerelement precisely on resonance due to changing factors, including of theamount of liquid in the reservoir decreasing during operation, thebias-pressure of the reservoir changing during operation, bubblespossibly forming on the nebulizer element, characteristics of the liquidbeing atomized, and/or the temperature of the nebulizer element varying.Such changing factors may result in one or more resonant frequencies ofthe nebulizer element increasing or decreasing. As such, a nebulizerelement that is attempted to be driven at a resonant frequency may havea less predictable flow rate of atomized liquid due to the nebulizerelement occasionally being driven off-resonance as the resonantfrequency of the nebulizer element changes. Rather, a more predictableflow rate may be obtained by intentionally driving the nebulizer elementoff-resonance at an operating frequency with a constant or near constantphase offset between the current and voltage of the drive signal.

A nebulizer element may be considered driven at a resonant frequencywhen there is no phase offset between the current and voltage of thedrive signal used to excite the nebulizer element. Driving the nebulizerelement at an off-resonance frequency may be desirable for severalreasons, including there being less variability in the flow rate ofatomized liquid from the nebulizer element if the resonant frequency ofthe nebulizer element drifts (such as due to changing operatingconditions of the nebulizer). At off-resonance frequencies, a phaseoffset between the current and voltage of the drive signal may bepresent. For example, driving a nebulizer element off-resonance with aphase offset of 30 degrees between the voltage waveform and the currentwaveform of the drive signal may produce a more consistent atomizationflow rate than if the nebulizer element was attempted to be driven at aresonant frequency with no phase offset between the voltage and currentof the drive signal. Maintaining an off-resonant frequency drive signalmay be useful regardless of whether a sealed drug reservoir is used.

Referring to sealed drug reservoirs, as the negative bias pressurewithin the drug reservoir changes (e.g., a greater difference betweenthe pressure inside the drug reservoir and the ambient pressure outsideof the drug reservoir is formed), the resonant frequency of thenebulizer element may change. In order to maintain the nebulizer elementvibrating at its resonant frequency, it may be necessary to change thefrequency of the waveform used to drive the nebulizer element.Similarly, a frequency at which a particular offset between the voltagewaveform and current waveform of the drive signal may vary as thenegative bias pressure within the drug reservoir changes. In order tomaintain the nebulizer element vibrating at the desired phase offset, itmay be necessary to change the frequency of the waveform used to drivethe nebulizer element.

Therefore, if a negative bias pressure occurs in the drug reservoir asliquid is drained during operation of the nebulizer, the frequency andmagnitude of the waveform used to drive the nebulizer element may needto vary as the negative bias pressure within the drug reservoir changesin order to maintain efficient operation of the nebulizer element,including maintaining consistent dosing of the liquid drug andconsistent droplet sizes.

To be clear, a sealed reservoir refers to a reservoir that prevents airfrom entering the reservoir as liquid is drained from the drugreservoir. It may, however, still be possible for air to enter thesealed drug reservoir through the holes in the nebulizer element. Thegreater the negative bias pressure (that is, the greater the differencebetween the pressure of the external environment and the pressure withinthe drug reservoir), the faster air may enter through holes in thenebulizer element.

FIG. 1A illustrates an embodiment of a possible nebulizer 100-a. Thenebulizer 100-a may include a nebulizer element 110, a drug reservoir120, a head space 130, an interface 140, and a cap 150. The nebulizerelement 110 may be comprised of a piezoelectric ring that may expand andcontract when an electric voltage is applied to the ring. The nebulizerelement 110 may be a vibrating nebulizer element. The piezoelectric ringmay be attached to a perforated membrane of the nebulizer element 110.Such a perforated membrane may have a number of holes passing throughit. When an electric voltage is applied to the piezoelectric ring, thismay cause the membrane to move and/or flex. Such movement of themembrane, while in contact with a liquid may cause the atomization(alternatively referred to as aerosolization) of the liquid.

A supply of a liquid, commonly a liquid drug, may be held in the drugreservoir 120. As illustrated, a drug reservoir is partially filled witha liquid drug. As the liquid drug is atomized, the amount of liquid drugremaining in the drug reservoir 120 may decrease. Depending on theamount of liquid drug in the drug reservoir 120, only a portion of thereservoir may be filled with liquid drug. The remaining portion of thedrug reservoir 120 may be filled with gas, such as air. This space iscommonly referred to as head space 130. An interface 140 may serve totransfer amounts of liquid drug between the drug reservoir 120 and thenebulizer element 110.

Nebulizers, and the techniques associated with such nebulizers, aredescribed generally in U.S. Pat. Nos. 5,164,740; 5,938,117; 5,586,550;5,758,637; 6,014,970; 6,085,740; 6,235,177; 6,615,824; 7,322,349, thecomplete disclosures of which are incorporated by reference for allpurposes.

A nebulizer with a sealed drug reservoir may be part of a larger system.The embodiment of FIG. 1B illustrates such a nebulizer system 100-b.FIG. 1B illustrates a nebulizer 151 with a sealed drug reservoirconnected to a driver 152. The sealed nebulizer illustrated in FIG. 1Bmay be the nebulizer of FIG. 1A, or may represent some other nebulizer.Driver 152 may control the rate and magnitude of vibration of thenebulizer element on nebulizer 151. Driver 152 may be connected to anelement of nebulizer 151 via cable 153. Driver 152 may regulate thevoltage and frequency of the signal provided to the nebulizer element ofnebulizer 151. The regulation of the voltage and frequency of the signalmay be based on the resonant frequency of the nebulizer element ofnebulizer 151. Such a signal may vary depending on the magnitude of thenegative bias pressure.

In some other embodiments of nebulizers, a driver may be incorporatedinto a handheld unit with the nebulizer. Nebulizer 100-c of FIG. 1Cillustrates an embodiment of a handheld nebulizer with an integrateddriver. Nebulizer 100-c may include a case 155, a mouthpiece 160, atrigger button 165, and an electrical plug 169. Case 155 may containsome or all of the elements found in other embodiments of nebulizers(such as nebulizer 100-a of FIG. 1A) and drivers (such as driver 152 ofFIG. 1B). Therefore, contained within case 155 may be a sealed drugreservoir and/or a device capable of generating an electrical signal ata voltage magnitude and frequency to vibrate an element that atomizesliquid stored in the drug reservoir. A person receiving the atomizedliquid drug may place her mouth on mouthpiece 160 and breathe in. Whilethe person receiving the atomized liquid drug is breathing in, she maypress trigger button 165 to trigger the element to begin aerosolizingliquid. In some embodiments, nebulizer 100-c may contain a sensor thatdetects when the person is breathing in and triggers the element tovibrate without trigger button 165 being necessary.

Nebulizer 100-c may also include an electrical plug 169. Electrical plug169 may be connected to an electrical outlet to power nebulizer 100-c.Nebulizer 100-c may contain a battery, thereby allowing electrical plug169 to be connected to an electrical outlet when nebulizer 100-c is notin use by a person, allowing a battery to be charged. Alternatively, insome embodiments of nebulizer 100-c, electrical plug 169 may need to beconnected to an electrical outlet while nebulizer 100-c is in use by aperson. In some embodiments, nebulizer 100-c may use replaceablebatteries as its power source.

In some embodiments, a nebulizer may operate in conjunction with aventilator. Nebulizer system 100-d in FIG. 1D illustrates a nebulizer178 that supplies atomized liquid drug to a person 176 via a ventilator170. Ventilator 170 may supply air suitable for breathing to person 176.Ventilator 170 may assist person 176 in breathing by forcing air intothe lungs of person 176 and then releasing air to mimic breathing. Whileperson 176 is using ventilator 170, it may be necessary to provideperson 176 with atomized liquid, such as a liquid drug.

Nebulizer 178 may be connected to a drug reservoir 186 that is sealed bya cap 180. Drug reservoir 186 may contain an amount of liquid drug 182.This liquid drug may be delivered to nebulizer 178 as liquid drug isatomized by nebulizer 178. As liquid drug is atomized, liquid drug 182may drain from drug reservoir 186, thereby increasing the volume ofheadspace 184. Headspace 184 may contain air. Headspace 184 may increasein volume, but may decrease in pressure as liquid drug 182 drainsbecause drug reservoir 186 allows no or minimal air into headspace 184.In some embodiments, drug reservoir 186 may not be sealed; as such thepressure may remain constant.

Driver 172, which may represent the same driver as driver 152 of FIG. 1B(or may represent some other driver), may deliver a signal to nebulizer178. This drive signal may control the vibration of an element ofnebulizer 178. Nebulizer 178 may be attached to a tube 179 used todeliver air and atomized liquid drug to person 176. Tube 179 mayterminate in a mask 174 covering the mouth and/or nose of person 176.The air and atomized liquid drug may then enter the airways of person176.

A nebulizer, such as those illustrated in FIGS. 1A-1D, may be connectedwith a driver such as illustrated in FIG. 2. FIG. 2 illustrates asimplified block diagram of a nebulizer system 200. The nebulizer 260may be the nebulizer 100-a of FIG. 1A or may represent some other formof nebulizer such as those in the referenced applications or FIGS.1B-1D. The nebulizer may be connected to the driver via a cable 270.Driver 210 may be driver 152 of FIG. 1B, or may be some other driver.Cable 270 may allow driver 210 to transmit an electrical waveform signal(the drive signal) of varying frequency and magnitude (of voltage)through cable 270 to drive an element of nebulizer 260.

Driver 210 may include an amplifier 230, a current phase shift detector240, a resonant frequency tracker 220, and a voltage profile 250. Basedupon the phase shift between the current supplied to nebulizer 260 andthe voltage generated by amplifier 230, the nebulizer element's resonantfrequency may be determined. From the resonant frequency, the negativebias pressure within the drug reservoir of the nebulizer may bedetermined, and the frequency and/or magnitude of the electricalwaveform signal driving nebulizer 260 may be adjusted.

The determination of the resonant frequency may be accomplished usingcurrent phase shift detector 240. Current phase shift detector 240monitors the phase shift between the phase of the current output byamplifier 230 to nebulizer 260 and the phase of the voltage output byamplifier 230 to nebulizer 260. Based upon the phase shift between thevoltage and current observed by current phase shift detector 240,resonant frequency tracker 220 outputs an output waveform to amplifier230 such that amplifier 230 outputs an electrical waveform signal withconstant or near constant phase shift between the voltage and current ofthe electrical waveform signal driving the element of nebulizer 260. Anelectrical waveform signal with constant (or near constant) phase shiftbetween the voltage and current of the electrical waveform signal mayrefer to the phase shift being held within a threshold range of thedesired phase shift, such as +/−0.5 degrees or +/−1 degree. To maintainthe constant or near constant phase shift, the frequency of the drivesignal may need to be adjusted as operating conditions of the nebulizerchanges. For example, during operation, the resonant frequencies (andthe phase offset at off-resonant frequencies) may change. As such, tomaintain a constant or near constant phase offset, the frequency of thedrive signal may be increased or decreased. This constant or nearconstant phase offset may be maintained for a period of time, such aswhile a liquid is being atomized by the nebulizer element.

As liquid is atomized and the bias pressure in the drug reservoirchanges, the resonant frequency of the nebulizer element may change.Further, factors besides the bias pressure within the sealed drugreservoir of the nebulizer 260 may change the nebulizer element'sresonant frequency. For example, the temperature of the nebulizerelement, excess liquid on the nebulizer element, and/or damage to thenebulizer element may cause a variation in the nebulizer element'sresonant frequency. However, it may be generally accepted that duringoperation, changes in the nebulizer element's resonant frequency isgenerally due to variations in the bias pressure within the drugreservoir of the nebulizer.

The resonant frequency and/or the measured change in resonant frequencymay be transmitted to voltage profile 250 by resonant frequency tracker220. Voltage profile 250 may be used to determine the proper magnitudeof voltage to apply to the nebulizer element at a particular resonantfrequency to maintain consistent droplet size and dosing of the atomizedliquid. In some embodiments, voltage profile 250 may include a table ofempirically gathered data. In such embodiments, the resonant frequencymay be located in the table, with a corresponding analog or digitalsignal being output to amplifier 230 that specifies the appropriatemagnitude of voltage amplifier 230 should output. For example, a tablemay include a predetermined voltage magnitude that may be communicatedto amplifier 230 when a particular resonant frequency is measured byresonant frequency tracker 220. Voltage profile 250 may also beexpressed as a graph of values, with the x-axis being frequency of thewaveform generated by resonant frequency tracker 220, and the y-axisrepresenting the appropriate voltage magnitude to be supplied toamplifier 230 such that amplifier 230 outputs an electrical signal ofcorrect magnitude.

A rough description of one set of possible values for voltage profile250 is that as the resonant frequency of the nebulizer elementincreases, the desired amplitude of the electrical signal output to thenebulizer will decrease. At a certain threshold, as the resonantfrequency continues to increase, the voltage will be held by voltageprofile 250 at a minimum level. In some embodiments of voltage profile250, the signal output to amplifier 230 is determined based on acalculation using the resonant frequency supplied by resonant frequencytracker 220.

The voltage profile may need to be modified or adjusted to accommodatethe characteristics (such as surface tension) of different liquidswithin the drug reservoir of the nebulizer. In some embodiments, aliquid drug, such as Amikacin, is used. In other embodiments, adifferent liquid drug or liquid (which may be other than a medicine) isused. In some embodiments, the voltage profiles necessary for a numberof liquids or liquid drugs may be similar enough that only one voltageprofile needs to be used for multiple liquids or liquid drugs. Modifyingor replacing voltage profile 250 may involve selecting a differentliquid via a user interface on driver 210 or loading different software,firmware, and/or hardware into driver 210.

Resonant frequency tracker 220 may transmit a waveform at or near thenebulizer element's current determined resonant frequency to amplifier230. Voltage profile 250 may transmit a signal indicating the desiredvoltage amplitude to be output by amplifier 230 to amplifier 230. Thissignal from voltage profile 250 may serve to control the gain of theamplifier 230. Based upon the input waveform from resonant frequencytracker 220 and the desired voltage amplitude received from voltageprofile 250, amplifier 230 generates an output electrical signal thatmay be used to drive an aperture plate of the nebulizer. Amplifier 230may be a variable gain linear power amplifier. In some embodiments, afixed gain power amplifier may be used in conjunction with a variablegain amplifier or a potentiometer. Further, various other amplifiers oramplifier-based circuits may be used to generate the output electricalsignal to drive nebulizer 260.

Current phase shift detector 240 may create a feedback loop to resonantfrequency tracker 220. Current phase shift detector 240 may determinethe phase shift of the current being output from the amplifier 230. Sucha phase shift may be transmitted to resonant frequency tracker 220,thereby allowing resonant frequency tracker 220 to either maintain thesame frequency signal (if the phase has not shifted), increase thefrequency, or decrease the frequency of the output signal in response tothe resonant frequency of the nebulizer element changing as the biaspressure within the sealed drug reservoir changes. Feedback throughcurrent phase shift detector 240 may allow driver 210 to periodically orcontinually adjust the magnitude and frequency of the electrical signaloutput to the nebulizer element while liquid is being atomized. This mayallow for any change in the bias pressure in the liquid reservoir to becontinually adjusted for by the driver.

It should be understood that various components of nebulizer system 200may be implemented using one or more processors and/or non-transitorycomputer-readable storage mediums. Referring to FIG. 2, variousillustrated components may be performed by a single processor ormultiple processors. For example, voltage profile 250 may be stored on acomputer-readable storage medium and may be accessed by a processor todetermine a gain that is provided to amplifier 230.

A driver, such as driver 210 of FIG. 2, may drive a nebulizer elementaccording to a method, such as method 300 of FIG. 3. Alternatively,method 300 may be performed using some other driver of a nebulizer.Method 300 may be performed using various different nebulizers, such asthe nebulizers of FIGS. 1A-1D, and FIG. 2. Method 300 may be used toadjust the frequency and/or magnitude of the drive signal used toenergize a nebulizer element and/or determine a lock-in frequency. Atstep 310, the driver may drive an element (also referred to as anaperture plate) of a nebulizer with an electrical signal (also referredto as a drive signal). This electrical signal may be a waveform beinggenerated at a particular frequency and magnitude.

At step 320, the phase shift between the voltage of the electricalsignal output to the nebulizer and the current of the electrical signalmay be measured. Using this phase shift, at step 330, the lock-infrequency of the nebulizer element may be determined. The frequency ofthe drive signal may need to be adjusted to determine the lock-infrequency. The lock-in frequency may be the frequency at which a targetphase offset occurs. The lock-in frequency may be the frequency at whichthe nebulizer element was driven to obtain the desired phase offsetbetween the current and voltage of the drive signal. Obtaining thelock-in frequency is further described in relation to FIG. 4. Aspreviously noted, the frequency at which the target phase offset occursmay shift over time as the negative bias pressure within the liquidreservoir of the nebulizer changes and/or other operating conditions ofthe nebulizer element changes.

At step 340, from the frequency determined at step 320, the biaspressure within the liquid reservoir may be determined at step 340. Insome embodiments, a value for the negative bias pressure is notdetermined. In some embodiments, a frequency difference value betweenthe current frequency used to drive the nebulizer element and apreviously determined lock-in frequency is determined. As such, thefrequency difference value calculated at step 340 may indicate theamount of frequency drift that has occurred to remain at the desiredcurrent-to-voltage phase offset.

At step 350, the magnitude of the voltage of the electrical signal usedto drive the nebulizer element may be determined. The magnitude may bedetermined using the resonant frequency determined at step 330 and/orthe negative bias pressure determined at step 340. The frequencydifference value that indicates the difference between the lock-infrequency and the current frequency being used to energize the nebulizerelement may be used to determine the voltage magnitude. The resonantfrequency, the determined frequency difference value, and/or thedetermined negative bias pressure may be used to consult a table ofvalues of a voltage profile. This table of values may specify theappropriate magnitude of voltage to be used for the electrical signaldriving the nebulizer element. Alternatively, the resonant frequency,the determined frequency difference value, and/or the determinednegative bias pressure may be used to calculate the appropriate voltagemagnitude to drive the nebulizer element. The appropriate magnitude maycorrespond to a magnitude intended to maintain a constant dosage rateand droplet size of the liquid being dispensed from the nebulizer. Thecalculations or table may vary depending on the properties of the liquidbeing dispensed. As such, a different calculation or table may be useddepending on the liquid or characteristics of the liquid being atomizedby the nebulizer element.

At step 360, the electrical waveform signal driving the nebulizerelement may be adjusted according to the frequency determined at step330 and/or the magnitude determined at step 350. The operating frequencyof the drive signal may be adjusted (e.g., increased or decreased) tomaintain the desired current-to-voltage phase offset at step 350. If theresonant frequency of the nebulizer element has not changed (and/or thefrequency at which the desired current-to-voltage phase offset has notchanged), the frequency and/or the magnitude of the electrical drivesignal driving the nebulizer element may not change. Method 300 mayrepeat while the nebulizer element is being driven by the driver.

A resonant frequency tracker, such as resonant frequency tracker 220 ofFIG. 2, may be used in various methods to determine and maintain a drivesignal at or near the resonant frequency of a nebulizer element, such asan element of nebulizer 260 of FIG. 2. Another form of frequencygenerator may be used to generate a frequency for the drive signal tomaintain a current-to-voltage phase offset. For example, driver 610 ofFIG. 6 may be used. FIG. 4 illustrates an embodiment of a method 400 fordetermining a resonant frequency of the nebulizer element and adjustingthe output electrical signal driving the nebulizer element based on thephase shift between the drive signals' voltage and current. Method 400of FIG. 4 may be implemented using resonant frequency tracker 220 ofFIG. 2, or may be implemented using some other resonant frequencytracker, be it implemented in software, firmware, and/or hardware. Itshould be understood that method 400 may be applied to maintaining aresonant frequency (corresponding to no current-to-phase offset) or anoff-resonance operating frequency (that corresponds to a particularcurrent-to-phase offset), such that a selected phase offset ismaintained between the current and voltage of the drive signal. A“lock-in frequency” refers to a frequency of the drive signal at whichthe desired current-to-voltage phase offset is initially detected. For aresonant frequency, this current-to-voltage phase offset may be zero,for operating off of resonance, the current-to-voltage phase offset maybe non-zero, such as thirty degrees.

If the resonant frequency or frequency with the desiredcurrent-to-voltage phase offset has not been determined or “locked on”to by a resonant frequency tracker, method 400 may be conducted. Theresonant frequency tracker may not have locked on to the resonantfrequency or the frequency with the desired current-to-voltage phaseoffset if, for example, the driver has just been turned on or activated,a new nebulizer is attached to the driver unit, the nebulizer elementhas been interfered with, or the nebulizer element has been damaged.

At step 411, the resonant frequency tracker may apply an infiniteimpulse response filter (“IIR filter”) to the phase signal received fromthe current phase shift detector. The IIR filter may be implementedusing analog and/or digital components. From this, a filtered phasevalue may be obtained. This filtered phase value may indicate thecurrent-to-voltage phase offset. The value may be an absolute value(thus not having a positive or negative sign attached to the value). Insome embodiments, the components necessary to determine a magnitude ofthe filtered phase value may tend to be more accurate in determining themagnitude than components that determine a signed value.

Using the filter phase value, the phase error between the filtered phaseand desired phase set point (which may be zero for a resonant frequencyor non-zero for off-resonance operation) may be determined at step 412.The determined phase error value may be used to determine if the errorhas been a smaller value than a predefined threshold for greater than apredefined period of time, such as one second, at step 413. In someembodiments, a different length of time is used, such as two seconds ora half second. Further, at step 413 it may be determined whether or notthe lock-in flag has been set.

If the error has been less than the threshold value for more than thepredefined period of time and the lock-in flag has not yet been set, thecurrent frequency of the signal output to the nebulizer is stored atstep 414 as the lock-in frequency. Further, the lock-in flag may be setto indicate that the lock-in frequency has been obtained at step 415.Returning to step 413, if the error has not been less than the thresholdvalue for more than the predefined period of time, method 400 mayproceed to step 411. While method 400 is being performed, anothermethod, such as method 800 or method 900, may be being performed thatadjusts the frequency of the drive signal. As such, when method 400 isrepeated, the result may vary due to changes in operatingcharacteristics of the nebulizer and changes in the frequency of thedrive signal.

In some embodiments, additional steps may be performed to determine ifthe current has passed a threshold. For example, if the current becomeslower than a predefined current threshold, it may be advantageous torestart a sweep to locate the lock-in frequency. At step 430, if theaverage current of the drive signal is less than some threshold currentvalue, the output voltage frequency and/or voltage magnitude of thedrive signal may be set to a start voltage frequency and voltagemagnitude at step 432. At step 434, the lock-in frequency determined bythe resonant frequency tracker may be reset to an initial value and thelock-in flag may be cleared. If the average current is not less than athreshold current value, steps 432 and 434 may not be performed in someembodiments.

Once the lock-in frequency has been determined, which may involvelock-in flag of step 414 being set, another method may be performed.FIG. 5 illustrates a method 500 for adjusting the voltage magnitude ofthe drive signal. Method 500 may be performed while maintaining thenebulizer element vibrating at a frequency having the desiredcurrent-to-voltage phase offset (which may be zero or non-zero). Method500 may represent a more detailed embodiment of step 350 of FIG. 3. Anerror rate value that indicates the amount of error between the presentfrequency of the drive signal and lock-in frequency may be determined atstep 521.

A determination of whether the present frequency of the drive signalbeing generated by the resonant frequency tracker is greater than thelock-in frequency of the nebulizer element may be made at step 522. Ifyes, at step 523, the output voltage may be scaled by a decay ratemultiplied by the error rate value determined at step 521. The rate ofchange of the voltage of the drive signal may be limited such that thevoltage is not changed at a rate above and/or below a threshold rate atstep 524. The output voltage may be limited to the end voltage at step525. This may prevent the output voltage from exceeding maximum and/orminimum threshold values. Next, method 500 may proceed to step 530. Ifthe present frequency is determined to not be greater than the resonantfrequency at step 522, the output voltage of the drive signal may be setto a start voltage at step 526, and method 500 may proceed to step 530.

Following steps 525 and 526, method 500 may repeat in order to controlthe magnitude of voltage output to the nebulizer element. In someembodiments, method 500 may proceed to step 530. At step 530, it may bedetermined if the current of the drive signal is less than a thresholdcurrent value. If so, the output voltage magnitude and frequency may beset to the start voltage at step 532 and the lock-in frequency may bereset at step 534.

In some embodiments, as discussed, rather than attempting to vibrate anebulizer element directly on a resonant frequency, it may be possibleto more accurately control an amount of liquid aerosolized if anebulizer is operated off-resonance. Operation with a zero degree phaseshift between the voltage and current of the drive signal transmitted tothe nebulizer element may be indicative of the nebulizer element beingvibrated at a resonant frequency. Rather than attempting to operate at azero degree phase between the current and voltage output by a nebulizerdriver, a phase offset, such as 30 degrees, may be maintained. Such aphase shift off of a resonant frequency of the nebulizer element mayresult in a more accurate dosage of an atomized medicine being deliveredto a patient. For example, if the resonant frequency of the nebulizerelement changes and some amount of phase offset drift occurs, the amountof liquid aerosolized may not vary significantly of the nebulizerelement is being energized at a non-resonant frequency. However, atand/or around zero degrees phase shift between the current and voltageof the drive signal, phase shift drift may result in a significantvariance in the amount of liquid aerosolized as the nebulizer elementsshifts from being energized at a resonant frequency to a non-resonantfrequency.

While some embodiments of a nebulizer may use a reservoir having anegatively-biased pressure, other embodiments of nebulizers may use areservoir to store liquid that is not negatively-biased. Embodiments ofFIGS. 6-9 may be used with or without a negatively-biased liquidreservoir. FIG. 6 illustrates a simplified block diagram of a nebulizersystem 600. Nebulizer system 600 may represent a more detailedembodiment of nebulizer system 200. As such, previously detailed methodsand systems may involve use of nebulizer system 600. Some components ofnebulizer system 600 may represent the same components as nebulizersystem 200. It should be understood that functions of at least some ofthe components of nebulizer system 200 and nebulizer system 600 may beperformed by processor 680 or some other processor. As such, nebulizersystem 600 may include one or more processors. Nebulizer system 600 mayalso contain a non-transitory computer-readable storage medium.

Nebulizer 660 may represent nebulizer 100-a of FIG. 1A or may representsome other nebulizer such as those in the referenced applications and/orin FIGS. 1B-1D. Nebulizer 660 may be connected to driver 610 via a cable670. Driver 610 may represent driver 152 of FIG. 1B or may be some otherdriver. Cable 670 may allow driver 610 to transmit an electricalwaveform signal of varying frequency and magnitude (of voltage) throughcable 670 to drive an element of nebulizer 660.

Driver 610 may include amplifier 630, a current-to-voltage phase shiftdetector 640, frequency generator 620, voltage profile 650, andprocessor 680. Based upon the phase shift between the current output tonebulizer 660 and the voltage output, the nebulizer element's resonantfrequency may be determined. It may be assumed that the resonantfrequency occurs when there is a zero degree phase difference betweenthe current and voltage outputs by amplifier 630.

The determination of the phase difference between the output voltage andoutput current may be performed by current-to-voltage phase shiftdetector 640. Current-to-voltage phase shift detector 640 may monitorthe phase shift between the phase of the current output by amplifier 630to nebulizer 660 and the phase of the voltage output by amplifier 630 tonebulizer 660. Based upon the phase shift between the voltage andcurrent observed by current-to-voltage phase shift detector 640, afrequency of a waveform output by frequency generator 620 may be changedby processor 680 such that amplifier 630 outputs an electrical waveformsignal with the predefined phase shift between the voltage and currentof the signal driving the element of nebulizer 660. Processor 680 maymonitor the phase shift indicated by current-to-voltage phase shiftdetector 640 and may provide an output to frequency generator 620 thatindicates whether the frequency should be held constant or changed. Itshould be understood that current-to-voltage phase shift detector 640and/or frequency generator 620 may be part of processor 680. In someembodiments, the phase shift detector communicates directly withfrequency generator 620.

On startup, processor 680 may cause frequency generator 620 to begingenerating a first predefined voltage start frequency and magnitude. Thefirst predefined frequency may be selected such that it is expected tobe less than the frequency of the desired phase offset for all or mostnebulizers. It should be understood that due to variances betweennebulizers and drivers, the precise frequency at which a particularphase offset occurs (and the frequencies at which resonant frequenciesoccur) may vary. The first predefined start frequency may be 122 kHz.Processor 680 may increase the frequency output by frequency generator620 until the target phase offset is indicated by current-to-voltagephase shift detector 640. If a second predefined frequency is reachedwithout the target phase offset being reached, the processor 680 maystart again by sweeping or stepping from the first predefined startfrequency. In some embodiments, the second predefined frequency is 145kHz. As such, it may have been previously determined, such as viaexperimentation, that the target phase offset occurs for all or almostall nebulizer elements in the range of when the operating frequency ofthe drive signal is between 122 kHz and 145 kHz. When the target phaseoffset is reached, processor 680 may cease causing the frequencygenerated by frequency generator 620 to increase or decrease.

In some embodiments, current-to-voltage phase shift detector 640 may notbe configured to identify whether a phase shift is positive or negative.In addition to causing a phase offset between the output voltage andcurrent to be maintained, processor 680 may determine whether variousother conditions have been satisfied. Processor 680 may determinewhether the impedance of nebulizer 660 is above or below a predefinedlimit. Also, processor 680 may determine whether the phase shift isincreasing or decreasing as the frequency output by frequency generator620 increases (or decreases). If at a frequency the target phase offsetis present, but the impedance of the nebulizer is not below (or above) athreshold and/or the phase offset is increasing as the frequency isincreasing (a positive slope), the processor 680 may ignore thefrequency and continue searching for another frequency within the rangedefined by the first and second predefined frequencies where each of theconditions is satisfied. Other embodiments may use a negative slope or aslope threshold for phase offset as a condition required to besatisfied.

In some embodiments, the frequency being generated by frequencygenerator 620 may be transmitted to voltage profile 650. Voltage profile650 may be used to determine the proper magnitude of voltage to outputto nebulizer 660 at a particular frequency to maintain consistentdroplet size and dosing of the atomized liquid. In some embodiments,voltage profile 650 may include a table of empirically gathered data. Insuch embodiments, frequencies may be indicated in the table, along withmagnitude values. An analog or digital signal may be output to amplifier630 that specifies the magnitude of voltage that amplifier 630 shouldoutput. For example, voltage profile 650 may include a predeterminedvoltage magnitude that may be communicated to amplifier 630 when aparticular frequency is generated by frequency generator 620. Voltageprofile 650 may also be expressed as a graph of values, with the x-axisbeing frequency of the waveform generated by frequency generator 620,and the y-axis representing the appropriate voltage magnitude to besupplied to amplifier 630 such that amplifier 630 outputs an electricalsignal of correct magnitude. Voltage profile 650 may be implemented aspart of processor 680.

The voltage profile may need to be modified or adjusted to accommodatethe characteristics (such as surface tension) of different liquidswithin the drug reservoir of the nebulizer. In some embodiments, aliquid drug, such as Amikacin, is used. In other embodiments, adifferent liquid drug or liquid is used. In some embodiments, thevoltage profiles for a number of liquids or liquid drugs may be similarenough that only one voltage profile needs to be used for multipleliquids or liquid drugs. Modifying or replacing voltage profile 650 mayinvolve selecting a different liquid via a user interface on driver 610or loading different software, firmware, and/or hardware into driver610.

Based upon the input waveform from frequency generator 620 and thedesired voltage amplitude received from voltage profile 650, amplifier630 may generate an output drive signal that may be used to drive anebulizer element, such as an aperture plate. Amplifier 630 may be avariable gain linear power amplifier. In some embodiments, a fixed gainpower amplifier may be used in conjunction with a variable gainamplifier or a potentiometer. Further, various other amplifiers oramplifier based circuits may be used to generate the output electricalsignal to drive nebulizer 660.

Current-to-voltage phase shift detector 640 may create a feedback loopto frequency generator 620 via processor 680. Current-to-voltage phaseshift detector 640 may determine the phase shift of the current tovoltage being output from the amplifier 630. Such a phase shift may beused to adjust the frequency output by frequency generator 620, therebyallowing frequency generator 620 to either maintain the same frequencysignal (e.g., to maintain a particular phase offset), increase thefrequency, or decrease the frequency of the output signal (e.g., toadjust the phase offset). Feedback through phase shift detector 640 mayallow driver 610 to periodically or continually adjust the magnitude andfrequency of the drive signal output to the nebulizer element whileliquid is being atomized. For example, if there is a change in biaspressure within a liquid reservoir (e.g., due to liquid evacuating thereservoir) feeding liquid to nebulizer 660, the frequency at which aparticular phase offset occurs may drift. This drift may be adjusted forby driver 610.

FIG. 7 illustrates an embodiment of a graph 700 showing phase offsetbetween drive signal voltage and drive signal current and impedance of anebulizer element at different voltage frequencies. Impedance 710indicates the impedance of a nebulizer element at various voltagefrequencies. Impedance 710 may be determined by measuring the currentand voltage applied to a nebulizer element, then using the measuredvalues to calculate the impedance. Phase offset 720 indicates phaseoffset between the voltage of the drive signal and the current of thedrive signal. This drive signal is used to excite the nebulizer elementand cause it to vibrate and atomize a liquid. The phase offset indicatedby phase offset 720 may be measured by a phase shift detector, such asphase shift detector 640 of FIG. 6.

Graph 700 illustrates the phase and impedance of a particular nebulizerelement at various voltage frequencies. It should be understood thatother nebulizer elements, including those which were attempted to bemanufactured to the same specifications as the nebulizer element used toproduce graph 700, may result in varying impedance and/or phase offsetvalues. As such, at a particular frequency, different nebulizer elementsmay exhibit different characteristics.

For the nebulizer element used to produce graph 700, it may be desirablefor the nebulizer element to be energized off a resonant frequency.While energizing on a resonant frequency may result in a greater amountof liquid being atomized, it may be difficult to continually excite thenebulizer element at the resonant frequency. One reason for this may bethat the resonant frequency of the nebulizer element may change asliquid is dispensed from a reservoir of the nebulizer. By energizing thenebulizer element off a resonant frequency, the amount of liquidatomized may be more easily regulated and maintained constant. Suchconsistency may be particularly important when the liquid beingnebulized is a medicine.

For the nebulizer element used to produce graph 700, it was previouslydetermined via testing the nebulizer element would be energized suchthat a 30° phase offset is maintained between the applied voltage andcurrent of the drive signal. Further, while characteristics may varyfrom nebulizer element to nebulizer element, nebulizer elements that aremanufactured according to a common specification may be expected to havecharacteristics similar enough such that the frequency at which thedesired phase delta occurs can be predicted to within a frequency range.This frequency range is indicated by frequency range 750. Frequencyrange 750 indicates a low-frequency and a high-frequency. Withinfrequency range 750, a frequency at which the target phase offset of 30°occurs may be attempted to be located. In other embodiments, avoltage-to-current phase offset of between 0 degrees and 60 degrees isused. In some embodiments, a voltage-to-current phase offset of between10 degrees and 70 degrees is used.

In some embodiments, scanning for the frequency at which the targetphase offset occurs may begin at the low-frequency of frequency range750. In the illustrated embodiment of graph 700, this low-frequency is122 kHz. At 122 kHz, the phase offset of the nebulizer element isapproximately 72°. Since this is not the 30° target phase offset thatwas predetermined, frequency scanning may occur. The frequency ofvoltage applied to the nebulizer element may be increased, eithercontinuously or by stepping. For example, steps of 250 Hz may be used.After each step, the phase offset between the current and voltage of thedrive signal may be determined. At 130 kHz, the target phase offset maybe realized in the illustrated embodiment of graph 700. Operating point740 indicates this frequency. Once this operating frequency has beenreached, the frequency of the voltage of the drive signal may no longerbe changed. Rather, the frequency may be maintained at the operatingpoint 740.

In graph 700, the first frequency at which a 30° phase offset exists isthe frequency to be used as operating point 740. However, withinfrequency range 750, it can be seen that multiple other frequencies havea phase offset of 30°. In graph 700, approximately 134 kHz, 137 kHz, and141 kHz also have a phase delta of 30°. If scanning the frequency range750 started down from the high frequency of frequency range 750 or the30° phase offset at 130 kHz was initially missed due to a scanningerror, one of these other instances of the 30° phase offset may first belocated. These other instances of a 30° phase offset may be lessdesirable due to atomization characteristics at those frequencies.

In addition to examining the phase offset, other characteristics of thedrive signal transmitted to the nebulizer element may be used in orderto determine if the desired operating point having the target phaseoffset has been reached. Other characteristics may include the impedanceof the nebulizer element and the slope of the phase offset. Referring toimpedance, a maximum and/or minimum impedance threshold may be definedsuch that if the target phase offset is realized but the nebulizerelement impedance does not meet the maximum and/or minimum impedancethreshold, scanning of frequency range 750 continues in an attempt tolocate another frequency where the target phase offset occurs. Referringto 141 kHz, a 30° phase offset exists; however impedance isapproximately 9000 ohms. Similarly, referring to 137 kHz, a 30° phaseoffset exists; however impedance is approximately 3000 ohms. A maximumimpedance threshold of, for example, 400 ohms would be exceeded ineither instance. Thus, 141 kHz and 137 kHz would not be used as theoperating point due to violation of a maximum impedance threshold of 400ohms.

Phase offset region 730, between approximately 133 kHz and 138 kHz,shows a local maximum in phase offset. It should be understood that thecomponents used to determine phase offset may only measure magnitude andnot sign (positive or negative), as such phase offset region 730 maycorrespond to phase offset that is negative. Accordingly, phase offset720 indicates a phase delta magnitude.

In addition to impedance thresholds, slope may be used to excludeparticular phase offsets matching the target phase offset withinfrequency range 750. Based on empirical evidence, it may be known that,at the desired operating point, the phase delta will be increasing ordecreasing as the voltage frequency of the drive signal is increased ordecreased. For the nebulizer element of graph 700, it may be known that,as frequency is increased, the magnitude of phase offset will bedecreasing at the desired operating point (i.e., phase offset 720 has anegative slope). As such, 134 kHz may be eliminated as a candidate forbeing the desired operating point. While 134 kHz may match the targetphase offset and may meet impedance thresholds, as frequency isincreasing so is the phase delta (i.e., the phase offset has a positiveslope).

In the embodiment of graph 700, only a single frequency within frequencyrange 750 satisfies the phase offset requirement, the maximum impedancethreshold, and the phase offset slope requirement. As such, onlyfrequency 130 kHz is eligible to be used as operating point 740. If,while scanning up through frequency range 750, 130 kHz is missed (e.g.,due to a scanning error), the high frequency of frequency range 750 maybe reached (145 kHz). At this point, scanning of frequencies may beginagain from the low frequency of frequency range 750.

Various methods may be performed that maintain a phase offset betweenthe current and voltage of a drive signal used to excite a nebulizerelement. FIG. 8 illustrates an embodiment of method 800 for locating andmaintaining a phase offset of a nebulizer drive signal. Method 800 maybe used to maintain various phase offsets between a current and voltageof a nebulizer element. For example, it may be possible to use method800 to maintain any non-zero phase offset between the current andvoltage of the nebulizer drive signal. In some embodiments, a targetphase offset of 30 degrees is desired between the current and voltage ofthe drive signal. The phase offset may be selected based on a previouslyidentified set-point that produces desirable atomization characteristicsby the nebulizer element (e.g., a high flow rate, little variation inflow rate if some frequency drift or phase offset drift occurs).

Method 800 may be performed with a nebulizer and a nebulizer driver. Forexample, nebulizer system 600 of FIG. 6 may be used to perform method800. Nebulizers such as those illustrated in FIGS. 1A-1D may be used inperforming method 800. Means for performing method 800 include thenebulizers and nebulizer drivers previously described.

At step 810, an indication of a target phase offset may be received.This target phase offset may be programmed into or otherwise stored bythe nebulizer drive. For example, phase shift detector 640 or processor680 of FIG. 6 may store an indication of the target phase offset that isdesired to be maintained between the current and voltage of the drivesignal applied to the nebulizer element. In some embodiments, the targetphase offset is non-zero. For example, the target phase offset is 30°. Azero phase offset may be associated with the nebulizer element operatingat a resonant frequency. The indication of the target phase offset maybe received by the nebulizer driver at the time of manufacture or whilebeing programmed or reprogrammed following manufacture. Additionally, atstep 810, a frequency range which indicates a minimum frequency and amaximum frequency may be received by the nebulizer system performingmethod 800. Within this frequency range, the driver may be permitted tovary the frequency of the drive signal to obtain the target phaseoffset.

At step 820, the nebulizer element may be energized with the drivesignal at a calculated frequency and calculated magnitude. During afirst iteration of method 800, an initial predefined frequency and apredefined amplitude may be used for the drive signal. From thepredefined frequency and predefined magnitude or the calculatedfrequency and calculated magnitude, the nebulizer driver may increase ordecrease the frequency of the drive signal until the target phase offsetis obtained. In the detailed embodiment of method 800, the frequency ofthe drive signal may be increased from the initial predefined frequencyuntil the desired phase offset is obtained. It should be understood thatin other embodiments the frequency may be decreased from the initialpredefined frequency. As example, referring to graph 700 of FIG. 7, theinitial predefined frequency may be 122 kHz. Accordingly, the initialpredefined frequency used for graph 700 is also the minimum frequency ofthe frequency range across which the drivers are permitted to vary thefrequency of the drive signal to obtain the target phase offset.

At step 830, the phase offset between the voltage and the current of thedrive signal used to energize the nebulizer element may be measured.Referring to nebulizer system 600 of FIG. 6, phase shift detector 640may measure the phase difference between the voltage and current of thedrive signal provided to an element of nebulizer 660.

The frequency of the drive signal that is to be applied to the nebulizerelement may be calculated at step 840. This may involve increasing thefrequency of the drive signal by a set amount. As such, the frequency ofthe drive signal may be increased in steps. In other embodiments ofmethod 800, the frequency of the drive signal may be continuouslyincreased until the target phase offset is reached. If a maximumfrequency of the frequency range across which the driver is permitted touse to excite the nebulizer element is reached, the frequency of thedrive signal may be decreased to the minimum frequency of frequencyrange. As an example of this, referring to graph 700, the frequency ofthe drive signal may be increased to 145 kHz. Once 145 kHz is reached,the frequency of the drive signal may be reset to 122 kHz. While theillustrated embodiment of method 800 involves increasing the frequencyof the drive signal across the frequency range, other embodiments mayinvolve decreasing frequency of the drive signal across the frequencyrange. Method 800 may repeat during operation of a nebulizer system tomaintain a particular phase offset. As such, during operation, method800 may beused to increase or decrease the frequency of the drive signalas necessary to maintain a predefined phase offset. In some embodiments,until a lock-in frequency is obtained, frequency may only be adjusted inone direction (e.g., increased). Once the lock-in frequency has beenobtained, frequency of the drive signal may be increased and/ordecreased to maintain the predefined phase offset.

FIG. 9 illustrates an embodiment of method 900 for maintaining a phaseoffset of a nebulizer drive signal. Method 900 may represent a moredetailed embodiment of method 800 of FIG. 8. Method 900 may be used tomaintain various phase offsets between a current and voltage of a drivesignal used to energize a nebulizer element. For example, it may bepossible to use method 900 to maintain various non-zero phase offsetsbetween the current and voltage of the nebulizer drive signal. In someembodiments, a phase offset of 30° is desired between the current andvoltage of the drive signal. The phase offset may be selected based on apreviously identified phase offset that produces desirable atomizationcharacteristics by the nebulizer element (e.g., a high flow rate, littlevariation in flow rate if some frequency drift or phase offset driftoccurs). Method 900 may be performed with a nebulizer and a nebulizerdriver. For example, nebulizer system 600 of FIG. 6 may be used toperform method 900. Nebulizers such as those illustrated in FIGS. 1A-1Dmay be used in performing method 900. Means for performing method 900include the nebulizers and nebulizer drivers previously described.

At step 910, an indication of a target phase offset may be received.This target phase offset may be programmed into or otherwise stored bythe nebulizer drive unit. For example, phase shift detector 640 orprocessor 680 of FIG. 6 may store an indication of the target phaseoffset that is desired to be maintained between the current and voltageof the drive signal applied to the nebulizer element. In manyembodiments, the target phase offset is non-zero. For example, thetarget phase offset could be 30°. A zero phase offset may be associatedwith the nebulizer element operating at one of its resonant frequencies.The indication of the target phase offset may be received by thenebulizer driver at the time of manufacture or while being programmed orreprogrammed following manufacture. Additionally, at step 910, afrequency range which indicates a minimum frequency and a maximumfrequency may be received. Within this frequency range, the driver maybe permitted to vary the frequency of the drive signal to obtain thetarget phase offset.

Further, at step 910 one or more additional evaluation criteria may bereceived and stored by the driver for use in determining whether afrequency should be locked onto once the target phase offset has beendetermined. Within the frequency range within which the driver ispermitted to vary the frequency of the drive signal, multiplefrequencies may exist at which the phase offset between the current andvoltage of the drive signal is equal to the target phase offset.However, only one of these phase offset points which match the targetphase offset may be desired for use as the operating point. For example,referring to graph 700 of FIG. 7, within frequency range 754 pointsexist where the phase offset is 30°. Additional evaluation criteriawhich may be used to determine the desired operating point may includeminimum and/or maximum impedance thresholds. Additional evaluationcriteria may also include a slope (e.g., positive, negative, orthreshold-based) of the phase offset and/or the impedance of thenebulizer element.

At step 920, during a first iteration of method 900, the nebulizerelement may be energized with the drive signal at an initial predefinedfrequency and a predefined amplitude. During subsequent iterations ofmethod 900, the nebulizer element may be energized with the drive signalat a calculated frequency and calculated amplitude based on phase offsetmeasurements. From the calculated or predefined frequency, the nebulizerdriver may increase or decrease the frequency of the drive signal untilthe target phase offset is obtained. In the illustrated embodiment ofmethod 900, the frequency of the drive signal is increased from theinitial predefined frequency until the lock-in frequency is obtained,then the frequency is increased and/or decreased as necessary tomaintain the phase offset. It should be understood that in otherembodiments the frequency may be decreased from the initial predefinedfrequency. As example, referring to graph 700 of FIG. 7, the initialpredefined frequency may be 122 kHz. Accordingly, the initial predefinedfrequency used for graph 700 is also the minimum frequency of thefrequency range across which the drivers permitted to vary the frequencyof the drive signal to obtain the target phase offset. Referring tonebulizer system 600, frequency generator 620 may create a waveformhaving a frequency as indicated by processor 680 and/or phase shiftdetector 640. The magnitude of the drive signal to be output may bedefined by voltage profile 650 in accordance with the frequency beinggenerated by frequency generator 620. Amplifier 630 may use the waveformfrom frequency generator 620 and the indication of amplitude fromvoltage profile 650 to create the drive signal, which is output tonebulizer 660.

At step 930, the phase offset between the voltage and the current of thedrive signal used to energize the nebulizer element may be measured.Referring to nebulizer system 600 of FIG. 6, for example, phase shiftdetector 640 may measure the phase difference between the voltage andcurrent of the drive signal output to nebulizer 660. Additionally atstep 930, the impedance of the nebulizer element may be measured (orcalculated). A calculation of the impedance of the nebulizer element maybe obtained using the current and voltage of the drive signal accordingto Ohm's law. Accordingly, the impedance of the nebulizer element may bedetermined at the nebulizer driver.

At step 935, a determination may be made as to whether the current ofthe drive signal is below a predefined threshold. If so, the frequencyof the drive signal may be increased (or decreased) according to amaximum predefined step size at step 936. Method 900 may then return tostep 920.

If the current is above the predefined threshold of step 935, method 900may proceed to step 940. At step 940, it may be determined if a phasedelta is less than a threshold amount. “Phase delta” refers to adifference in magnitude between the target phase offset and the measuredphase offset. If it is determined that the phase delta is not within apredefined threshold range of the target phase offset, such as 1°, 2°,3°, 4°, 5°, 10° (or some other threshold range, method 900 may proceedto step 960. If it is determined that the phase delta is within thepredefined threshold range of the target phase offset, a low gain modeflag may be set at step 941, then method 900 may proceed to step 960.

Further, at step 940, the additional evaluation criteria may beevaluated. This may involve determining if a minimum and/or maximumthreshold impedance is satisfied. Additionally, the slope of the phaseoffset and/or the slope of the impedance may be determined. The slopemay be determined by comparison of one or more of the previouslymeasured impedance and/or phase offset measurements to the currentlymeasured impedance and/or phase offset measurements. Whether the slopeis positive or negative may serve as an evaluation criteria. A slopemagnitude may also serve as an evaluation criteria. If the frequency ofthe drive signal is being increased and the phase offset is alsoincreasing, this may be evidence of a positive slope. For example,referring to graph 700 of FIG. 7, such a positive slope of phase offsetis present around 133 kHz. If the frequency of the drive signal is beingincreased and the phase offset is decreasing, this is evidence of anegative phase offset slope. Again, referring to graph 700, such anegative slope is present in the vicinity of 130 kHz. Regardless ofwhether the phase delta is less than the threshold value, if theadditional evaluation criteria at step 940 are not satisfied, method 900may proceed to step 960. At step 960, the impedance and/or phase offsetvalue measured may be stored. These stored values may later be used fordetermination of the slope of the nebulizer element's impedance and/orthe slope of the phase offset.

If at step 960 it is determined that the low gain mode flag has not beenset, method 900 may proceed to step 961. At step 961, the current phaseoffset value and/or the impedance of the nebulizer element (based on thevoltage and current of the drive signal) may be stored, such as for aslope calculation of impedance or phase offset. The adjustment offrequency at step 962 may occur as part of a “high gain” mode. Becauseat step 940 it was determined that the target phase offset was notwithin a predefined threshold, it may be expected that a significantchange in frequency will need to occur before the target phase offset isrealized. Adjustment of the frequency at step 962 in the high gain modemay permit for faster scanning/stepping of frequencies. In someembodiments, high gain mode may involve a larger frequency step sizebeing used for adjustment than a “low gain” mode. As such, at step 962,the frequency may be increased by a large step, such as 250 Hz.Following step 962, the newly calculated frequency (and possiblyamplitude) for the drive signal may be used to energize the nebulizerelement at step 920 and the phase offset (and the impedance) of thenebulizer element may again be measured at step 930.

At step 962, if a maximum frequency of the frequency range across whichthe driver is permitted to use to excite the nebulizer element isreached, the frequency of the drive signal may be set to the minimumfrequency of frequency range. As an example of this, referring to graph700, the frequency of the drive signal may be increased to 145 kHz. Once145 kHz is reached, the frequency of the drive signal may be reset to122 kHz. While the illustrated embodiment of method 900 involvesincreasing the frequency of the drive signal across the frequency range,other embodiments may involve decreasing frequency of the drive signalacross the frequency range.

Returning to step 940, if it is determined the phase delta is less thana threshold amount and the low gain mode flag was set at step 941,method 900 may proceed to step 965 following step 960. At step 965 thephase offset value and/or the impedance of the nebulizer element may bestored. These stored values may be used for determination of the slopeof the nebulizer elements impedance and/or the slope of the phaseoffset. If the phase delta is zero, this means that the measured phaseoffset at step 930 is equal to the target phase offset.

The adjustment of frequency at step 966 may occur as part of a “lowgain” mode. Because at step 940 it was determined that the target phaseoffset was within a threshold range of the target phase offset, it maybe expected that only a small change in frequency will need to occurbefore the target phase offset is realized. Adjustment of the frequencyat step 966 in the low gain mode may permit for more precisescanning/stepping of frequencies. In some embodiments, low gain mode mayinvolve a smaller frequency step size being used for adjustment than the“high gain” mode. As such, at step 966, the frequency may be increasedby a small step, such as 50 Hz. Following step 966, the phase offset(and the impedance) of the nebulizer element may again be measured atstep 930. If the phase delta is zero, no frequency adjustment may benecessary at step 966.

While a wide variety of drugs, liquids, liquid drugs, and drugsdissolved in liquid may be aerosolized, the following provides extensiveexamples of what may be aerosolized. Additional examples are provided inU.S. application Ser. No. 12/341,780, the entire disclosure of which isincorporated herein for all purposes. Nearly any anti-gram-negative,anti-gram-positive antibiotic, or combinations thereof may be used.Additionally, antibiotics may comprise those having broad spectrumeffectiveness, or mixed spectrum effectiveness. Antifungals, such aspolyene materials, in particular, amphotericin B are also suitable foruse herein. Examples of anti-gram-negative antibiotics or salts thereofinclude, but are not limited to, aminoglycosides or salts thereof.Examples of aminoglycosides or salts thereof include gentamicin,amikacin, kanamycin, streptomycin, neomycin, netilmicin, paramecin,tobramycin, salts thereof, and combinations thereof. For instance,gentamicin sulfate is the sulfate salt, or a mixture of such salts, ofthe antibiotic substances produced by the growth of Micromonosporapurpurea. Gentamicin sulfate, USP, may be obtained from Fujian FukangPharmaceutical Co., LTD, Fuzhou, China. Amikacin is typically suppliedas a sulfate salt, and can be obtained, for example, from Bristol-MyersSquibb. Amikacin may include related substances such as kanamicin.

Examples of anti-gram-positive antibiotics or salts thereof include, butare not limited to, macrolides or salts thereof. Examples of macrolidesor salts thereof include, but are not limited to, vancomycin,erythromycin, clarithromycin, azithromycin, salts thereof, andcombinations thereof. For instance, vancomycin hydrochloride is ahydrochloride salt of vancomycin, an antibiotic produced by certainstrains of Amycolatopsis orientalis, previously designated Streptomycesorientalis. Vancomycin hydrochloride is a mixture of related substancesconsisting principally of the monohydrochloride of vancomycin B. Likeall glycopeptide antibiotics, vancomycin hydrochloride contains acentral core heptapeptide. Vancomycin hydrochloride, USP, may beobtained from Alpharma, Copenhagen, Denmark.

In some embodiments, the composition comprises an antibiotic and one ormore additional active agents. The additional active agent describedherein includes an agent, drug, or compound, which provides somepharmacologic, often beneficial, effect. This includes foods, foodsupplements, nutrients, drugs, vaccines, vitamins, and other beneficialagents. As used herein, the terms further include any physiologically orpharmacologically active substance that produces a localized or systemiceffect in a patient. An active agent for incorporation in thepharmaceutical formulation described herein may be an inorganic or anorganic compound, including, without limitation, drugs which act on: theperipheral nerves, adrenergic receptors, cholinergic receptors, theskeletal muscles, the cardiovascular system, smooth muscles, the bloodcirculatory system, synoptic sites, neuroeffector junctional sites,endocrine and hormone systems, the immunological system, thereproductive system, the skeletal system, autacoid systems, thealimentary and excretory systems, the histamine system, and the centralnervous system.

Examples of additional active agents include, but are not limited to,anti-inflammatory agents, bronchodilators, and combinations thereof.

Examples of bronchodilators include, but are not limited to, β-agonists,anti-muscarinic agents, steroids, and combinations thereof. Forinstance, the steroid may comprise albuterol, such as albuterol sulfate.

Active agents may comprise, for example, hypnotics and sedatives,psychic energizers, tranquilizers, respiratory drugs, anticonvulsants,muscle relaxants, antiparkinson agents (dopamine antagnonists),analgesics, anti-inflammatories, antianxiety drugs (anxiolytics),appetite suppressants, antimigraine agents, muscle contractants,additional anti-infectives (antivirals, antifungals, vaccines)antiarthritics, antimalarials, antiemetics, anepileptics, cytokines,growth factors, anti-cancer agents, antithrombotic agents,antihypertensives, cardiovascular drugs, antiarrhythmics, antioxicants,anti-asthma agents, hormonal agents including contraceptives,sympathomimetics, diuretics, lipid regulating agents, antiandrogenicagents, antiparasitics, anticoagulants, neoplastics, antineoplastics,hypoglycemics, nutritional agents and supplements, growth supplements,antienteritis agents, vaccines, antibodies, diagnostic agents, andcontrasting agents. The active agent, when administered by inhalation,may act locally or systemically.

The active agent may fall into one of a number of structural classes,including but not limited to small molecules, peptides, polypeptides,proteins, polysaccharides, steroids, proteins capable of elicitingphysiological effects, nucleotides, oligonucleotides, polynucleotides,fats, electrolytes, and the like.

Examples of active agents suitable for use in this invention include butare not limited to one or more of calcitonin, amphotericin B,erythropoietin (EPO), Factor VIII, Factor IX, ceredase, cerezyme,cyclosporin, granulocyte colony stimulating factor (GCSF),thrombopoietin (TPO), alpha-1 proteinase inhibitor, elcatonin,granulocyte macrophage colony stimulating factor (GMCSF), growthhormone, human growth hormone (HGH), growth hormone releasing hormone(GHRH), heparin, low molecular weight heparin (LMWH), interferon alpha,interferon beta, interferon gamma, interleukin-1 receptor,interleukin-2, interleukin-1 receptor antagonist, interleukin-3,interleukin-4, interleukin-6, luteinizing hormone releasing hormone(LHRH), factor IX, insulin, pro-insulin, insulin analogues (e.g.,mono-acylated insulin as described in U.S. Pat. No. 5,922,675, which isincorporated herein by reference in its entirety), amylin, C-peptide,somatostatin, somatostatin analogs including octreotide, vasopressin,follicle stimulating hormone (FSH), insulin-like growth factor (IGF),insulintropin, macrophage colony stimulating factor (M-CSF), nervegrowth factor (NGF), tissue growth factors, keratinocyte growth factor(KGF), glial growth factor (GGF), tumor necrosis factor (TNF),endothelial growth factors, parathyroid hormone (PTH), glucagon-likepeptide thymosin alpha 1, IIb/IIIa inhibitor, alpha-1 antitrypsin,phosphodiesterase (PDE) compounds, VLA-4 inhibitors, bisphosphonates,respiratory syncytial virus antibody, cystic fibrosis transmembraneregulator (CFTR) gene, deoxyreibonuclease (Dnase),bactericidal/permeability increasing protein (BPI), anti-CMV antibody, 13-cis retinoic acid, oleandomycin, troleandomycin, roxithromycin,clarithromycin, davercin, azithromycin, flurithromycin, dirithromycin,josamycin, spiromycin, midecamycin, leucomycin, miocamycin, rokitamycin,andazithromycin, and swinolide A; fluoroquinolones such asciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, alatrofloxacin,moxifloxicin, norfloxacin, enoxacin, grepafloxacin, gatifloxacin,lomefloxacin, sparfloxacin, temafloxacin, pefloxacin, amifloxacin,fleroxacin, tosufloxacin, prulifloxacin, irloxacin, pazufloxacin,clinafloxacin, and sitafloxacin, teicoplanin, rampolanin, mideplanin,colistin, daptomycin, gramicidin, colistimethate, polymixins such aspolymixin B, capreomycin, bacitracin, penems; penicillins includingpenicllinase-sensitive agents like penicillin G, penicillin V,penicillinase-resistant agents like methicillin, oxacillin, cloxacillin,dicloxacillin, floxacillin, nafcillin; gram negative microorganismactive agents like ampicillin, amoxicillin, and hetacillin, cillin, andgalampicillin; antipseudomonal penicillins like carbenicillin,ticarcillin, azlocillin, mezlocillin, and piperacillin; cephalosporinslike cefpodoxime, cefprozil, ceftbuten, ceftizoxime, ceftriaxone,cephalothin, cephapirin, cephalexin, cephradrine, cefoxitin,cefamandole, cefazolin, cephaloridine, cefaclor, cefadroxil,cephaloglycin, cefuroxime, ceforanide, cefotaxime, cefatrizine,cephacetrile, cefepime, cefixime, cefonicid, cefoperazone, cefotetan,cefinetazole, ceftazidime, loracarbef, and moxalactam, monobactams likeaztreonam; and carbapenems such as imipenem, meropenem, pentamidineisethiouate, lidocaine, metaproterenol sulfate, beclomethasonediprepionate, triamcinolone acetamide, budesonide acetonide,fluticasone, ipratropium bromide, flunisolide, cromolyn sodium,ergotamine tartrate and where applicable, analogues, agonists,antagonists, inhibitors, and pharmaceutically acceptable salt forms ofthe above. In reference to peptides and proteins, the invention isintended to encompass synthetic, native, glycosylated, unglycosylated,pegylated forms, and biologically active fragments, derivatives, andanalogs thereof.

Active agents for use in the invention further include nucleic acids, asbare nucleic acid molecules, vectors, associated viral particles,plasmid DNA or RNA or other nucleic acid constructions of a typesuitable for transfection or transformation of cells, i.e., suitable forgene therapy including antisense. Further, an active agent may compriselive attenuated or killed viruses suitable for use as vaccines. Otheruseful drugs include those listed within the Physician's Desk Reference(most recent edition), which is incorporated herein by reference in itsentirety.

The amount of antibiotic or other active agent in the pharmaceuticalformulation will be that amount necessary to deliver a therapeuticallyor prophylactically effective amount of the active agent per unit doseto achieve the desired result. In practice, this will vary widelydepending upon the particular agent, its activity, the severity of thecondition to be treated, the patient population, dosing requirements,and the desired therapeutic effect. The composition will generallycontain anywhere from about 1 wt % to about 99 wt %, such as from about2 wt % to about 95 wt %, or from about 5 wt % to 85 wt %, of the activeagent, and will also depend upon the relative amounts of additivescontained in the composition. The compositions of the invention areparticularly useful for active agents that are delivered in doses offrom 0.001 mg/day to 100 mg/day, such as in doses from 0.01 mg/day to 75mg/day, or in doses from 0.10 mg/day to 50 mg/day. It is to beunderstood that more than one active agent may be incorporated into theformulations described herein and that the use of the term “agent” in noway excludes the use of two or more such agents.

Generally, the compositions are free of excessive excipients. In one ormore embodiments, the aqueous composition consists essentially of theanti-gram-negative antibiotic, such as amikacin, or gentamicin or both,and/or salts thereof and water.

Further, in one or more embodiments, the aqueous composition ispreservative-free. In this regard, the aqueous composition may bemethylparaben-free and/or propylparaben-free. Still further, the aqueouscomposition may be saline-free.

In one or more embodiments, the compositions comprise an anti-infectiveand an excipient. The compositions may comprise a pharmaceuticallyacceptable excipient or carrier which may be taken into the lungs withno significant adverse toxicological effects to the subject, andparticularly to the lungs of the subject. In addition to the activeagent, a pharmaceutical formulation may optionally include one or morepharmaceutical excipients which are suitable for pulmonaryadministration. These excipients, if present, are generally present inthe composition in amounts sufficient to perform their intendedfunction, such as stability, surface modification, enhancingeffectiveness or delivery of the composition or the like. Thus, ifpresent, excipient may range from about 0.01 wt % to about 95 wt %, suchas from about 0.5 wt % to about 80 wt %, from about 1 wt % to about 60wt %. Preferably, such excipients will, in part, serve to furtherimprove the features of the active agent composition, for example byproviding more efficient and reproducible delivery of the active agentand/or facilitating manufacturing. One or more excipients may also beprovided to serve as bulking agents when it is desired to reduce theconcentration of active agent in the formulation.

For instance, the compositions may include one or more osmolalityadjuster, such as sodium chloride. For instance, sodium chloride may beadded to solutions of vancomycin hydrochloride to adjust the osmolalityof the solution. In one or more embodiments, an aqueous compositionconsists essentially of the anti-gram-positive antibiotic, such asvancomycin hydrochloride, the osmolality adjuster, and water.

Pharmaceutical excipients and additives useful in the presentpharmaceutical formulation include but are not limited to amino acids,peptides, proteins, non-biological polymers, biological polymers,carbohydrates, such as sugars, derivatized sugars such as alditols,aldonic acids, esterified sugars, and sugar polymers, which may bepresent singly or in combination.

Exemplary protein excipients include albumins such as human serumalbumin (HSA), recombinant human albumin (rHA), gelatin, casein,hemoglobin, and the like. Suitable amino acids (outside of thedileucyl-peptides of the invention), which may also function in abuffering capacity, include alanine, glycine, arginine, betaine,histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine,isoleucine, valine, methionine, phenylalanine, aspartame, tyrosine,tryptophan, and the like. Preferred are amino acids and polypeptidesthat function as dispersing agents. Amino acids falling into thiscategory include hydrophobic amino acids such as leucine, valine,isoleucine, tryptophan, alanine, methionine, phenylalanine, tyrosine,histidine, and proline.

Carbohydrate excipients suitable for use in the invention include, forexample, monosaccharides such as fructose, maltose, galactose, glucose,D-mannose, sorbose, and the like; disaccharides, such as lactose,sucrose, trehalose, cellobiose, and the like; polysaccharides, such asraffinose, melezitose, maltodextrins, dextrans, starches, and the like;and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitolsorbitol (glucitol), pyranosyl sorbitol, myoinositol and the like.

The pharmaceutical formulation may also comprise a buffer or a pHadjusting agent, typically a salt prepared from an organic acid or base.Representative buffers comprise organic acid salts of citric acid,ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinicacid, acetic acid, or phthalic acid, Tris, tromethamine hydrochloride,or phosphate buffers.

The pharmaceutical formulation may also include polymericexcipients/additives, e.g., polyvinylpyrrolidones, celluloses andderivatized celluloses such as hydroxymethylcellulose,hydroxyethylcellulose, and hydroxypropylmethylcellulose, Ficolls (apolymeric sugar), hydroxyethylstarch, dextrates (e.g., cyclodextrins,such as 2-hydroxypropyl-.beta.-cyclodextrin andsulfobutylether-.beta.-cyclodextrin), polyethylene glycols, and pectin.

The pharmaceutical formulation may further include flavoring agents,taste-masking agents, inorganic salts (for example sodium chloride),antimicrobial agents (for example benzalkonium chloride), sweeteners,antioxidants, antistatic agents, surfactants (for example polysorbatessuch as “TWEEN 20” and “TWEEN 80”), sorbitan esters, lipids (for examplephospholipids such as lecithin and other phosphatidylcholines,phosphatidylethanolamines), fatty acids and fatty esters, steroids (forexample cholesterol), and chelating agents (for example EDTA, zinc andother such suitable cations). Other pharmaceutical excipients and/oradditives suitable for use in the compositions according to theinvention are listed in “Remington: The Science & Practice of Pharmacy”,19.sup.th ed., Williams & Williams, (1995), and in the “Physician's DeskReference”, 52.sup.nd ed., Medical Economics, Montvale, N.J. (1998),both of which are incorporated herein by reference in their entireties.

It should be noted that the methods, systems, and devices discussedabove are intended merely to be examples. It must be stressed thatvarious embodiments may omit, substitute, or add various procedures orcomponents as appropriate. For instance, it should be appreciated that,in alternative embodiments, the methods may be performed in an orderdifferent from that described, and that various steps may be added,omitted, or combined. Also, features described with respect to certainembodiments may be combined in various other embodiments. Differentaspects and elements of the embodiments may be combined in a similarmanner. Also, it should be emphasized that technology evolves and, thus,many of the elements are examples and should not be interpreted to limitthe scope of the invention.

Specific details are given in the description to provide a thoroughunderstanding of the embodiments. However, it will be understood by oneof ordinary skill in the art that the embodiments may be practicedwithout these specific details. For example, well-known processes,algorithms, structures, and techniques have been shown withoutunnecessary detail in order to avoid obscuring the embodiments. Thisdescription provides example embodiments only, and is not intended tolimit the scope, applicability, or configuration of the invention.Rather, the preceding description of the embodiments will provide thoseskilled in the art with an enabling description for implementingembodiments of the invention. Various changes may be made in thefunction and arrangement of elements without departing from the spiritand scope of the invention.

Further, the preceding description generally details aerosolizing liquiddrugs. However, it should be understood that liquids besides liquiddrugs may be aerosolized using similar devices and methods.

Also, it is noted that the embodiments may be described as a processwhich is depicted as a flow diagram or block diagram. Although each maydescribe the operations as a sequential process, many of the operationscan be performed in parallel or concurrently. In addition, the order ofthe operations may be rearranged. A process may have additional stepsnot included in the figure.

What is claimed is:
 1. A nebulizer system, the nebulizer systemcomprising: a liquid reservoir for storing liquid; a nebulizer,comprising a nebulizer element having a plurality of apertures, wherein:the nebulizer element is vibrated to atomize liquid from the liquidreservoir; and the nebulizer element is driven by a drive signal; adriver that outputs the drive signal, the driver comprising: a frequencygenerator; a phase shift detector configured to measure a phase offsetindicative of a phase difference between a voltage of the drive signaland a current of the drive signal; and a processing system configuredto: determine a phase delta indicative of a difference between anon-zero target phase offset and the measured phase offset; change afrequency of the drive signal that is output by the frequency generatorto decrease the phase delta; and adjust a voltage magnitude of the drivesignal used to drive the nebulizer element, wherein adjusting thevoltage magnitude compensates for a change in flow rate caused by adecrease in pressure developing within the liquid reservoir as liquid isatomized.
 2. The nebulizer system of claim 1, wherein the processingsystem is further configured to change the frequency of the drive signalthat is output by the frequency generator to decrease the phase deltacomprises the processing system being configured to: change thefrequency of the drive signal that is output by the frequency generatorto decrease the phase delta to less than a threshold phase delta in ahigh gain mode, wherein while in the high gain mode the processingsystem performs larger frequency adjustments than while operating in alow gain mode; after changing the frequency of the drive signal in thehigh gain mode, determine the phase delta is less than the thresholdphase delta; and change the frequency of the drive signal that is outputby the frequency generator to decrease the phase delta using the lowgain mode based on determining the phase delta is less than thethreshold phase delta.
 3. The nebulizer system of claim 2, wherein theprocessing system is further configured to determine a slope of thephase offset as the frequency of the drive signal is changed.
 4. Thenebulizer system of claim 3, wherein the processing system operating inthe low gain mode to change the frequency of the drive signal that isoutput by the frequency generator is conditioned on the slope of thephase offset being negative as frequency increases.
 5. The nebulizersystem of claim 1, wherein the processing system is further configuredto calculate an impedance of the nebulizer element using the voltage ofthe drive signal and the current of the drive signal.
 6. The nebulizersystem of claim 5, wherein the processing system changing the frequencyof the drive signal in the low gain mode is conditioned on the impedanceof the nebulizer element being below a stored impedance threshold. 7.The nebulizer system of claim 1, wherein the threshold phase delta isfive degrees or less.
 8. The nebulizer system of claim 11, wherein thetarget phase offset between 25 degrees and 35 degrees.
 9. The nebulizersystem of claim 1, wherein the processing system is further configuredto limit changing of the voltage magnitude by a stored threshold ratesuch that the voltage magnitude is not decreased at a rate greater thanthe stored threshold rate.
 10. A nebulizer apparatus, the nebulizerapparatus comprising: a liquid storage means; a nebulizer meanscomprising a vibratable means having a plurality of apertures, wherein:the vibratable means is vibrated to atomize liquid from the liquidstorage means; and the vibratable means is driven by a drive signal; adriver means that outputs the drive signal, the driver means comprising:a frequency generation means; a phase shift detection means thatmeasures a phase offset indicative of a phase difference between avoltage of the drive signal and a current of the drive signal; and aprocessing means configured to: determine a phase delta indicative of adifference between a non-zero target phase offset and the measured phaseoffset; change a frequency of the drive signal that is output by thefrequency generator to decrease the phase delta; and adjust a voltagemagnitude of the drive signal used to drive the vibratable means,wherein adjusting the voltage magnitude compensates for a change in flowrate caused by a decrease in pressure developing within the liquidstorage means.
 11. The nebulizer apparatus of claim 10, wherein theprocessing means is further configured to change the frequency of thedrive signal that is output by the frequency generator to decrease thephase delta comprises the processing means being configured to: changethe frequency of the drive signal that is output by the frequencygeneration means to decrease the phase delta to less than a thresholdphase delta in a high gain mode, wherein while in the high gain mode theprocessing means performs larger frequency adjustments than whileoperating in a low gain mode; after changing the frequency of the drivesignal in the high gain mode, determine the phase delta is less than thethreshold phase delta; and change the frequency of the drive signal thatis output by the frequency generation means to decrease the phase deltausing the low gain mode based on determining the phase delta is lessthan the threshold phase delta.
 12. The nebulizer apparatus of claim 10,wherein the processing means is further configured to determine a slopeof the phase offset as the frequency of the drive signal is changed. 13.The nebulizer apparatus of claim 12, wherein the processing meansoperating in the low gain mode to change the frequency of the drivesignal that is output by the frequency generation means is conditionedon the slope of the phase offset being negative as frequency increases.14. The nebulizer apparatus of claim 10, wherein the threshold phasedelta is five degrees or less.
 15. The nebulizer apparatus of claim 14,wherein the target phase offset between 25 degrees and 35 degrees.
 16. Amethod for atomizing liquid, the method comprising: storing, using aliquid reservoir of a nebulizer system, a liquid; outputting, by anebulizer driver to a nebulizer element, a drive signal having afrequency and a magnitude; vibrating the nebulizer element comprising aplurality of apertures to atomize liquid from the liquid reservoir, thenebulizer element being caused to vibrate by the drive signal; measuringa phase offset of the drive signal, the phase offset being indicative ofa phase difference between a voltage of the drive signal and a currentof the drive signal; determining a phase delta indicative of adifference between a non-zero target phase offset and the measured phaseoffset; changing a frequency of the drive signal to decrease the phasedelta; and adjusting a voltage magnitude of the drive signal tocompensate for a change in flow rate caused by a decrease in pressuredeveloping within the liquid reservoir as liquid is atomized by thenebulizer element.
 17. The method for atomizing liquid of claim 16,wherein changing the frequency of the drive signal to decrease the phasedelta comprises: changing the frequency of the drive signal to decreasethe phase delta to less than a threshold phase delta in a high gainmode, wherein while in the high gain mode the processing system performslarger frequency step size adjustments than while operating in a lowgain mode; after changing the frequency of the drive signal in the highgain mode, determining the phase delta is less than the threshold phasedelta; and after changing the frequency of the drive signal in the highgain mode and determining the phase delta is less than the thresholdphase delta, changing the frequency of the drive signal to decrease thephase delta using the low gain mode.
 18. The method for atomizing liquidof claim 16, further comprising: determining a slope of the phase offsetas the frequency of the drive signal is changed, wherein changing modefrom the high gain mode to the low gain mode is conditioned on the slopeof the phase offset being negative as frequency increases.
 19. Themethod for atomizing liquid of claim 16, wherein the threshold phasedelta is five degrees or less.
 20. The method for atomizing liquid ofclaim 19, wherein the target phase offset between 25 degrees and 35degrees.